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This study evaluates combination strategies to overcome that resistance. Pemigatinib, a selective FGFR1–3 inhibitor, shows significant Bliss synergy with KRAS G12C inhibitors. Reduced KRAS G12C dependency follows decreased FGFR1 activity in mesenchymal-like cells. Knockdown confirms FGFR1’s key role, while xenograft models with mesenchymal phenotype and high FGFR1 expression respond to the combination in nonsmall cell lung cancer.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-fgfr-inhibitor-pemigatinib-overcomes-cancer-drug-resistance-to-kras-g12c-inhibitors-in-mesenchymal-lung-cancer/374689/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/the-fgfr-inhibitor-pemigatinib-overcomes-cancer-drug-resistance-to-kras-g12c-inhibitors-in-mesenchymal-lung-cancer/374689.png","ImageObject",300,407,{"name":92,"@type":93},"Pentious","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What combination did the study investigate to address KRAS G12C inhibitor resistance?","Question",{"text":112,"@type":113},"The study investigated combining pemigatinib with KRAS G12C inhibitors to overcome resistance and improve therapeutic response.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why is FGFR1 important in the synergy with KRAS G12C inhibitors?",{"text":117,"@type":113},"Pemigatinib produced synergy with KRAS G12C inhibitors, and experiments showed FGFR1 activity decreases KRAS G12C dependency. Knockdown experiments verified that FGFR1, but not FGFR2–4, is important for the synergistic effect.",{"name":119,"@type":110,"acceptedAnswer":120},"What patient-relevant models were used to support the combination’s effectiveness?",{"text":121,"@type":113},"Human lung cancer xenograft and patient-derived xenograft models with mesenchymal phenotype and high FGFR1 expression were sensitive to the combination of KRAS G12C inhibitors and pemigatinib.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},374689,1790641997,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},1374404730887,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","OPEN ACCESS  \nCitation: Abdollahi A, Favata M, Weber M, Roman V, Hess R, Hammond K, et al. (2025) The FGFR inhibitor pemigatinib overcomes cancer drug resistance to KRAS G12C inhibitors in mesenchymal lung cancer. PLoSOne 20(8): e0327588. [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pone.0327588](journal.pone.0327588)  \nEditor: Asmerom Tesfamariam Sengal, QUT Health: Queensland University of Technology Faculty of Health, AUSTRALIA  \nReceived: July 16, 2024  \nAccepted: June 17, 2025  \nPublished: August 11, 2025  \nCopyright: © 2025 Abdollahi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nData availability statement: All data are fully available in the main text or Supporting  Information. Original images for blots and gels are in S1_raw_images and original figures with underlying values for plotted data and reported  \nRESEARCH ARTICLE  \nThe FGFR inhibitor pemigatinib overcomes cancer drug resistance to KRAS G12C inhibitors in mesenchymal lung cancer  \nAngela Abdollahi, Margaret Favata, Michael Weber, Valerie Roman, Rodrigo Hess, Kayla Hammond, Matthew R. Farren, Mike Schaffer, Aidan Gilmartin, Hui Wang, Jonathan Rios-Doria*, Alejandro Amador-Arjona  \nIncyte Research Institute, Wilmington, Delaware, United States of America  \n* [j](jdoria@incyte.com)[doria@incyte.com](jdoria@incyte.com)  \nAbstract  \nKRAS mutations are high prevalence oncogenic drivers for multiple cancers. With the advent of new classes of KRAS inhibitors that are showing meaningful clinical activity, research is now turning to questions of optimal combinations of therapies for specific indications, as many patients with KRAS G12C mutations do not respond and/or develop resistance to single-agent treatment. Here, we investigate combination therapies that may overcome resistance to KRAS G12C inhibitors. We found that pemigatinib, a potent and selective FGFR1–3 inhibitor, had a significantly high Bliss synergy score in combination with KRAS G12C inhibitors, and FGFR1 activity was shown to decrease KRAS G12C-dependency conferring inherent resistance in mesenchymal-like cell lines. Knockdown experiments verified the importance of FGFR1, but not FGFR2-4, for the synergistic effect with KRAS G12C inhibitors. Additionally, human lung cancer xenograft and patient-derived xenograft models with a mesenchymal phenotype and high FGFR1 expression were sensitive to the combination of G12C inhibitors and pemigatinib. In short, we demonstrate that pemigatiniband KRAS G12C inhibitors are promising agents for combination therapy in nonsmall cell lung cancer with a mesenchymal-like phenotype harboring high FGFR1 expression and KRAS G12C mutations to broaden patient response.  \nIntroduction  \nKRAS is the most frequently mutated oncogene in human cancer, accounting for roughly 30% of non-small cell lung cancer (NSCLC) cases [ 1] . KRAS is a guanosine triphosphatase (GTPase) that functions in the transduction of signals downstream from activated receptors at the cell membrane to promote migration, survival, and differentiation of the cell. When functioning normally, KRAS cyclically switches from the guanosine diphosphate (GDP)-bound inactive state to the GTP-bound active state,  \nPLOS One | [https://doi.org/10.1371/journal.pone.0327588](https://doi.org/10.1371/journal.pone.0327588) August 11, 2025 1 / 16  \nmeasures are in S1_raw_figures available in Supporting Information.  \nFunding: This work was funded by Incyte Corporation, Wilmington, DE, USA. The sponsor had a role in the study design, data collection and analysis, and decision to develop and publish the manuscript.  \nCompeting interests: All authors are employees and stockholders of Incyte Corporation, Wilmington, DE, USA. This does not alter our adherence to PLOS ONE policies on sharing da","cbCaiqm0N9muW5jF","https://ap.wps.com/l/cbCaiqm0N9muW5jF","pdf",1558774,16,"English","# Abstract\n# Introduction\n## KRAS as an oncogenic driver in NSCLC\n## KRAS G12C inhibitors and resistance mechanisms","[{\"question\":\"What combination did the study investigate to address KRAS G12C inhibitor resistance?\",\"answer\":\"The study investigated combining pemigatinib with KRAS G12C inhibitors to overcome resistance and improve therapeutic response.\"},{\"question\":\"Why is FGFR1 important in the synergy with KRAS G12C inhibitors?\",\"answer\":\"Pemigatinib produced synergy with KRAS G12C inhibitors, and experiments showed FGFR1 activity decreases KRAS G12C dependency. Knockdown experiments verified that FGFR1, but not FGFR2–4, is important for the synergistic effect.\"},{\"question\":\"What patient-relevant models were used to support the combination’s effectiveness?\",\"answer\":\"Human lung cancer xenograft and patient-derived xenograft models with mesenchymal phenotype and high FGFR1 expression were sensitive to the combination of KRAS G12C inhibitors and pemigatinib.\"}]","The FGFR inhibitor pemigatinib overcomes cancer drug resistance to KRAS G12C inhibitors in mesenchymal lung cancer | PDF",1790202184]